Asthma is a chronic inflammatory disorder of the airways affecting the world population in epidemic proportions. Indeed, approximately five percent of the world population is affected. This means that over 15 million Americans, and hundreds of millions of others worldwide, are susceptible. In the United States, over 400,000 hospitalizations for asthma were required during 1994, and over 1.9 million asthma related emergency room visits were made during 1995. Over 5,000 asthma related deaths occur in the United States each year. See http://www.asthmainamerica.com (Oct. 15, 1999).
In susceptible individuals, asthma causes recurrent episodes of coughing, wheezing, chest tightness, and difficult breathing. Inflammation makes airways sensitive to stimuli such as allergens, chemical irritants, tobacco smoke, cold air and exercise. When exposed to such stimuli, airways may become swollen, constricted, filled with mucus, and hyper responsive to stimuli.
There currently is no cure for asthma, but two types of treatments that suppress asthma symptoms and prevent attacks are currently used by many asthma sufferers. One of these types of treatments employs quick-relief medications, such as inhaled bronchodilator therapy, which works quickly to suppress symptoms by relaxing airway smooth muscle. The other of these types of treatments employs long-term preventive medications, such as inhaled, oral, or intramuscular corticosteroids, and leukotriene antagonists, which can prevent the onset of symptoms and attacks by controlling the underlying inflammation, thereby keeping persistent asthma under control. Unfortunately, many of the preventive medications have undesirable side effects, such as serious as growth limitation in children, osteoporosis, weight gain, and cataracts. As a result, the failure to properly identify the amount of inflammation in the airways, and therefore the appropriate treatment for a subject' asthmatic condition, may significantly adversely impact the subject' health. To date, however, there is no generally accepted manner of readily determining whether a given patient requires treatment, let alone what specific type of treatment should be used.
Conventionally, asthma is diagnosed by examining a number of indicators and qualitatively assessing the observed results. For example, a clinical diagnosis of asthma is often prompted by a combination of symptoms such as episodic breathlessness, wheezing, chest tightness, and coughing. However, these symptoms often occur only nocturnally and therefore are difficult for a doctor to monitor or measure. In addition, recently manifested symptoms alone are neither diagnostic indicators for asthma nor true measures of severity, so doctors must often evaluate a patient' health over long time periods before a diagnosis of asthma may be made with reasonable confidence. Because of the difficulty inherent in diagnosing asthma, doctors must use a patient's response to asthma treatments as a diagnostic tool. For example, the fact that bronchodilator treatment results in the relief of symptoms generally associated with asthma could indicate the presence of asthma. Disadvantageously, such diagnosis methods may result in the unnecessary application of asthma medications that have undesirable side effects. Accordingly, it would be desirable to have a device and method for readily diagnosing asthma before engaging in a course of treatment.
After a physician has covered the difficult ground of determining whether a person suffers from asthma, the physician must go through another process to determine the degree of severity of the asthma in order to prescribe an appropriate course of treatment. As with the diagnosis of asthma generally, there currently is no simple or noninvasive way to measure the degree of inflammation. There also is no objective method for determining when a course of treatment for airway inflammation can be discontinued. Accordingly, it would be desirable to have a device and method for simply, non-invasively and accurately determining the degree or severity of an asthmatic condition, and to what degree, if at all, a chosen course of treatment will be, or has been, effective.
In the past, few devices and methods for diagnosing asthma have been proposed, and those that have been proposed have not met with success. U.S. Pat. No. 5,922,610 to Alving, et al., issued Jul. 13, 1999, discloses a system and method for diagnosing inflammatory respiratory disorders related to abnormal nitric oxide (NO) levels in exhaled breathing air. The approach of the '610 patent includes a mask into which a subject may breathe, filters for removing substances present in the exhaled air that may interfere with NO measurement, and an instrument which receives the uncondensed exhaled air and uses a chemiluminescence technique to measure the NO level of the exhalate. The approach of the '610 patent therefore is very different from that of the present invention, which is drawn to diagnosing and treating respiratory diseases such as asthma by monitoring the acetic acid concentrations of breath samples, including exhaled breath condensate samples exhalate.
Other devices and methods have been proposed which collect a breath sample for diagnostic purposes, but like the '610 patent, none of these proposals teach or suggest testing a breath sample for acetic acid/acetate concentrations to diagnose asthma or other respiratory or other diseases. For example, European Patent No. 0759169, published Nov. 23, 1995 (published with English translation of claims only), discloses a process and device for collecting expired breath content, which may later be evaluated to determine the condition and metabolic performance of organs such as the lungs and the respiratory system. Among other significant differences between the present invention and the approach of the '169 patent, the latter does not appear to contemplate any specific respiratory disorders, such as asthma, in connection with which the disclosed device and process may be useful, nor does it appear to teach or suggest testing condensed breath exhalate for acetic acid/acetate concentrations as an indicator of any respiratory disease or other disease. Similarly, U.S. Pat. No. 5,081,871 to Glaser, issued Jan. 21, 1992, discloses an apparatus and method for collecting human exhaled breath for later analysis to determine whether the sample contains harmful substances such as volatile solvents, volatile compounds, endogenous compounds, volatile endogenously produced or used compounds, toxic chemicals, organic solvents, and natural air gasses. The '871 patent does not relate to the collection and testing of a breath condensate, nor does it teach or suggest testing exhalate for acidity or ammonium acetic acid/acetate concentrations to diagnose respiratory diseases. In addition, the device and method of the '871 patent are substantially different from those of the present invention.
The ability to monitor conditions in the lung is important in the management of respiratory disease. Currently, peak flow measurements, spirometry and other indirect methods are often used to measure lung function. Results from these tests are used to evaluate the patient's condition and subsequent testing is aimed at monitoring disease progression. Unfortunately, these tests are often effort dependent and open to inconsistent results.
Acetic acid is a volatile compound produced in the airway through a number of pathways. Some pathways include, but are not limited to, eukaryotic acetycholinesterase, and eukaryotic or prokaryotic aldehyde dehydrogenases. One source of acetic acid in the breath is from the breakdown and clearing of ethanol from the body. The presence of acetic acid in the airway of patients with respiratory disease has not been previously described or associated with respiratory disease states.
The present invention is based on the determination that acetic acid and/or acetate levels have a large impact on exhaled breath condensate pH and are involved in the respiratory disease symptoms. In particular, applicants assert that the relative level of acetic acid and/or acetate in the airway can be monitored and used in the diagnosis, management and treatment of respiratory disease.
Other devices for collecting exhaled breath are shown in International Application No. PCT/US01/13895 to Baddour, filed Apr. 30, 2001 and U.S. Pat. No. 6,033,368 to Gaston et al., filed Mar. 28, 1996, which are hereby incorporated by reference herein in their entirety.